Unraveling redox pathways of the disulfide bond in dimethyl disulfide: Ab initio modeling.

Context: In cellular environments, the reduction of disulfide bonds is pivotal for protein folding and synthesis. However, the intricate enzymatic mechanisms governing this process remain poorly understood. This study addresses this gap by investigating a disulfide bridge reduction reaction, serving as a model for comprehending electron and proton transfer in biological systems. Six potential mechanisms for reducing the dimethyl disulfide (DMDS) bridge through electron and proton capture were explored. Thermodynamic and kinetic analyses elucidated the sequence of proton and electron addition. MD-PMM, a method that combines molecular dynamics simulations and quantum-chemical calculations, was employed to compute the redox potential of the mechanism. This research provides valuable insights into the mechanisms and redox potentials involved in disulfide bridge reduction within proteins, offering an understanding of phenomena that are challenging to explore experimentally.

Methods: All calculations used the Gaussian 09 software package at the MP2/6-311 + g(d,p) theory level. Visualization of the molecular orbitals and electron densities was conducted using Gaussview6. Molecular dynamics simulations were performed using GROMACS with the CHARMM36 force field. The PyMM program (Python Program for QM/MM Simulations Based on the Perturbed Matrix Method) is used to apply the Perturbed Matrix Method to MD simulations.